The central theme of the application for a Boston Center for Intervention Development and Applied Research (CIDAR) is "Vulnerability to Progression in Schizophrenia". We see two major strengths of the proposal. First we study subjects who are at various stages of progression of the disorder, prodromal, first episode and chronic, giving us a broad perspective and large database on phenotypic markers and predictors of progression. Moreover, prodromes and first episode individuals will be evaluated in a prospective longitudinal study. A second major strength, in our view, is our plan to link clinical, cognitive, neuroimaging, electrophysiological, hormonal and genetic markers of SZ disease progression to the understanding of how the underlying neural circuits may be disturbed. We do this by investigating the expression of genes of interest in specific cellular populations in post-mortem material and evaluating genetic association of the relevant genes with progression indices from each Project. Four projects, each with an experienced investigator as PI, all evaluate the same group of subjects so as to bring multiple perspectives on the markers and predictors of progression. Project 1. "Functional anatomy of neurocognitive deterioration in schizophrenia", uses neuropsychological and fMRI evaluations. Project 2, "Hormones, memory &sex effects in illness progression in schizophrenia", evaluates hormones and gender differences in schizophrenia. Project 3, "Electrophysiological and MRI gray matter markers and predictors of progression", uses event-related potentials (ERPs) and MRI gray matter measures to evaluate progression, often conjoint, in these two domains. Project 4, "Vulnerability to white matter progression in schizophrenia" uses diffusion tensor imaging evaluations of white matter. A long-standing history of previous successful collaborations and work on joint projects by these project PIs will facilitate the synergistic interactions essential for knitting together data from the different methodological and conceptual domains. The Center mechanism brings added value to this work since no single R01 award could support: 1) the translational gene expression and genetics endeavor in the cores that specifically links to each Project's clinical research findings;2) the large-scale subject recruiting needed for each project;3) the extensive neuroimaging work;4) the linking together of the Project's diverse technologies and levels of analysis on the same subjects, affording a rich opportunity to understand interrelationships of findings from different domains.